Introduction
Olfactory dysfunctions represent one of the most frequent and specific symptoms of coronavirus disease 2019 (Covid-19), affecting approximately 50 to 85 per cent of patients.Reference Vaira, Lechien, Khalife, Petrocelli, Hans and Distinguin1–Reference Lechien, Ducarme, Place, Chiesa-Estomba, Khalife and De Riu5 Taste and smell dysfunctions, which are characteristic of the earliest stages of Covid-19, generally regress spontaneously within 15 days.Reference Lechien, Journe, Hans, Chiesa-Estomba, Mustin and Beckers6,Reference Chary, Carsuzaa, Trijolet, Capitaine, Roncato-Saberan and Fouet7 However, some authors have reported the persistence of severe chemosensitive dysfunctions in patients who were evaluated for more than 30 days after the clinical onset.Reference Kosugi, Lavinsky, Romano, Fornazieri, Luz-Matsumoto and Lessa8–Reference Vaira, Hopkins, Petrocelli, Lechien, Soma and Giovanditto10 The long-term chemosensitive recovery rate has not yet been fully clarified because there have been only four studies in the literature with a follow up of six months from the first appearance of the disorder.Reference Lechien, Chiesa-Estomba, Beckers, Mustin, Ducarme and Journe11–Reference Boscolo-Rizzo, Menegaldo, Fabbris, Spinato, Borsetto and Vaira14 Such a long period of observation is necessary to understand the incidence of any permanent chemosensitive disorders because some authors have found that there are margins for recovery even two months after the clinical onset,Reference Le Bon, Pisarski, Verbeke, Prunier, Cavalier and Thill15,Reference Vaira, Hopkins, Petrocelli, Lechien, Chiesa-Estomba and Salzano16 and in some forms of post-viral anosmia, recovery times of more than one year have been reported.Reference Lee, Lee, Wee and Kim17
In June 2020, we published the results of a chemosensitive psychophysical evaluation of a large series of 300 Covid-19 patients within the first seven days after the development of the disorder.Reference Petrocelli, Ruggiero, Baietti, Pandolfi, Salzano and Salzano18 The purpose of this second report was to establish the functional recovery rate by objectively re-evaluating these patients one, two, three and six months later.
Materials and methods
This prospective study represents the continuation of the report previously published by our research group which involved 300 Covid-19 out-patients who had undergone psychophysical evaluation of smell and taste within seven days of the clinical onset.Reference Petrocelli, Ruggiero, Baietti, Pandolfi, Salzano and Salzano18 The study included adult patients diagnosed with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection confirmed by real-time polymerase chain reaction on a nasopharyngeal swab and who had not experienced any previous taste or smell disturbances, neurological disease, chronic rhinosinusitis, or a history of oral or nasal cancer, surgery, radiotherapy or trauma. All study participants were patients of the healthcare staff of the Bellaria and Maggiore Hospital, Bologna, Italy, and were followed by the Surveillance and Prevention Department of the Bellaria and Maggiore Hospital.
After the first evaluation, the patients were re-evaluated at one, two, three and six months. The study protocol was approved by the AUSL Bologna Ethical Committee (approval number: 378-2020-OSS-AUSLBO). The smell and taste functions of all the patients were remotely assessed by means of the self-administered psychophysical test proposed and validated by Vaira et al.Reference Vaira, Salzano, Petrocelli, Deiana, Salzano and De Riu19–Reference Vaira, Hopkins, Salzano, Petrocelli, Melis and Cucurullo21 The telephone interviews started with the request for an explicit consent to participate in the study. Next, the patient's demographics (i.e. age, gender and professional role), comorbidities or conditions that could be a reason for exclusion from the study were recorded. The presence of other Covid-19 symptoms and the date of onset were also noted for each patient.
All the patients were contacted by telephone by the same team of researchers who had explained the preparation of the odorants and flavoured solutions and guided the patients during the self-administration of the test. The test methodology and the scoring system have already been extensively described in previous studies.Reference Petrocelli, Ruggiero, Baietti, Pandolfi, Salzano and Salzano18–Reference Vaira, Hopkins, Salzano, Petrocelli, Melis and Cucurullo21
The olfactory test included the evaluation of the ethyl alcohol olfactory threshold and the discriminative function for six groups of common household odorants. The score thus obtained ranges from 0 (anosmia) to 100 (normal olfactory function), allowing a classification of the olfactory function of the patients into five clinical categories: anosmia (scores between 0 and 10), severe hyposmia (scores between 20 and 40), moderate hyposmia (scores between 50 and 60), mild hyposmia (scores between 70 and 80) and a normal sense of smell (scores between 90–100).
The gustatory function was assessed by means of four solutions, one for each primary taste. The taste score ranged from 0 (ageusia) to 4 (a normal perception), allowing a classification of the patients into five clinical categories: ageusia (score 0), severe hypogeusia (score 1), moderate hypogeusia (score 2), mild hypogeusia (score 3) and a normal sense of taste (score 4).
The statistical analysis was performed using SPSS® statistical software. Categorical variables were reported in numerals and percentages of the total. Descriptive statistics for quantitative variables are given as the mean and standard deviation or median (interquartile range). The Wilcoxon signed rank test for paired data was performed to evaluate the statistical significance of any changes in olfactory and gustatory scores during the observation period. Cross-tabulation analysis and the Fisher's exact tests were used to evaluate the significance of the correlations between the chemosensitive disorders and general and clinical variables. The level of statistical significance was set at p ≤ 0.05 with a 95 per cent confidence interval.
Results
All of the 300 patients included in the first study completed the six-month follow up. The general and clinical features of the patients are reported in Table 1.
Table 1. General and clinical features of the study population
SD = standard deviation; IQR = interquartile range; CI = confidence interval
At baseline, 190 (63.3 per cent) and 184 (61.3 per cent) of patients experienced olfactory or gustatory dysfunction, respectively (Figures 1 and 2). The disorders presented were mostly severe, with psychophysical scores referable to anosmia in 47 per cent of cases and complete ageusia detected in 38 per cent of the patients. The improvement in olfactory function was significant at the two-month follow up. The psychophysical scores did not change significantly at the subsequent control times (Table 2). At the end of the observation period, 81 patients (27 per cent) still experienced a persistent olfactory disturbance, including anosmia in 15 cases (5 per cent; Figure 1).
Fig. 1. Olfactory clinical diagnosis and score trend during the observation period.
Fig. 2. Gustatory clinical diagnosis and score trend during the observation period.
Table 2. Chemosensitive trend score analysis
Each p-value refers to the analysis of the differences in the median olfactory score between the observation time considered and the one immediately preceding. IQR = interquartile range
As for taste, the improvement in the psychophysical scores was significant only between the baseline and the 30-day control (Table 2). The mean score curve therefore reached a plateau with non-significant variations in subsequent control times. At the 6-month evaluation, 30 patients (10 per cent) presented with a persistent gustatory disturbance with an incidence of complete ageusia of 1 per cent (3 cases; Figure 2). The statistical association between the clinical and epidemiological characteristics of the patients and the presence of persistent disturbances of smell (Table 3) and taste (Table 4) was significant only between age and the persistence of the olfactory dysfunction (odds ratio, 41.5; 95 per cent confidence interval, 19.4–8.8; p < 0.001).
Table 3. Olfactory logistic regression and cross-tabulation analysis results
DV = dependent variable; IV = independent variable; CI = confidence interval
Table 4. Gustatory logistic regression and cross-tabulation analysis results
DV = dependent variable; IV = independent variable; CI = confidence interval
Discussion
Persistent olfactory and gustatory disorders are emerging as one of the most frequent long-term morbidities of SARS-CoV-2 infection. The first long-term prospective studies report the persistence of severe disorders at 6-month follow up in around 10 per cent of patients who had previously been affected by Covid-19. Such a high prevalence in the population means that over the next few years a huge number of patients will seek assistance for the treatment of this disabling long-term morbidity. For this reason, it is essential to identify specific therapies that can prevent the chronicity of chemosensitive disorders in Covid-19 patients.Reference Vaira, Hopkins, Petrocelli, Lechien, Cutrupi and Salzano22,Reference Le Bon, Konopnicki, Pisarski, Prunier, Lechien and Horoi23
However, to achieve this goal it is necessary to establish the exact frequency of long-term dysfunction to understand if there are any clinical or epidemiological risk factors and, above all, to identify the temporal cut-off points beyond which there is no longer likelihood for significant improvements in olfactory and gustatory function. These cut-off points may therefore represent the time when specific therapy is certainly indicated. The very few studies published so far on this topic have the limitation of being based solely on patient interviewsReference Hopkins, Surda, Vaira, Lechien, Safarian and Saussez12 or with regard to studies based on psychophysical tests, of not presenting intermediate evaluations.Reference Lechien, Chiesa-Estomba, Beckers, Mustin, Ducarme and Journe11,Reference Niklassen, Draf, Huart, Hintschich, Bocksberger and Trecca13
One of the strengths of this study was that the baseline was set within seven days of the onset of symptoms and before any recovery from chemosensory dysfunction had begun. In this way, it was possible to establish the exact prevalence of olfactory and gustatory disorders in the early stages of Covid-19 and to provide a reliable basis for the prospective evaluation. During the infection, 210 patients (70 per cent) had at least one chemosensory dysfunction. These were mainly severe disorders with a prevalence of anosmia and ageusia of 47 per cent and 38 per cent, respectively. This frequency is in line with that reported in other previously published psychophysical studies.Reference Vaira, Lechien, Khalife, Petrocelli, Hans and Distinguin1,Reference Lechien, Chiesa-Estomba, Vaira, De Riu, Cammaroto and Idrissi3,Reference Spinato, Fabbris, Polesel, Cazzador, Borsetto and Hopkins4,Reference Chary, Carsuzaa, Trijolet, Capitaine, Roncato-Saberan and Fouet7,Reference Vaira, Hopkins, Petrocelli, Lechien, Chiesa-Estomba and Salzano16,Reference Petrocelli, Ruggiero, Baietti, Pandolfi, Salzano and Salzano18,Reference Vaira, Deiana, Fois, Pirina, Madeddu and De Vito20,Reference Vaira, Hopkins, Salzano, Petrocelli, Melis and Cucurullo21,Reference Speth, Singer-Cornelius, Oberle, Gengler, Brockmeier and Sedaghat24–Reference Vaira, Lechien, Salzano, Salzano, Maglitto and Saussez26 Regarding any functional recovery over time, the average olfactory score showed statistically significant improvements within two months after clinical onset. The curve then flattened without any significant improvements in the subsequent controls. On the other hand, taste showed an earlier recovery with significantly better scores at the 30-day control and a plateau without any further improvement in the subsequent controls.
This is the first prospective study with a six-month follow up that presents intermediate evaluations. For this reason, to the best of our knowledge there are no data in the literature to provide the baseline to enable us to carry out a meta-analysis. Previous studies, with a two-month follow up,Reference Le Bon, Pisarski, Verbeke, Prunier, Cavalier and Thill15,Reference Vaira, Hopkins, Petrocelli, Lechien, Chiesa-Estomba and Salzano16 had suggested the possibility of a later functional recovery. However, this possibility seems to be excluded on the basis of an analysis of our results. In our series, all patients presenting with anosmia or ageusia at two months continued to experience this severe disorder until the end of the observation period.
At the 6-month evaluation, 27 per cent and 10 per cent of the patients had residual olfactory or gustatory disturbance, respectively. Any evaluation of this prevalence must certainly be performed while taking into account the fact that mild olfactory dysfunctions are present in about 15 per cent of the general population.Reference Whitcroft and Hummel27 At the same time, the high frequency of persistent anosmia (5 per cent) and ageusia (3 per cent) found in our series of patients should be emphasised. This prevalence of severe olfactory disturbances is similar to that reported in the studies by Lechien et al.Reference Lechien, Chiesa-Estomba, Beckers, Mustin, Ducarme and Journe11 and Boscolo-Rizzo et al. Reference Boscolo-Rizzo, Menegaldo, Fabbris, Spinato, Borsetto and Vaira14 but higher than the 1 per cent found by Niklassen et al.Reference Niklassen, Draf, Huart, Hintschich, Bocksberger and Trecca13 Taste function at 6 months post-infection was previously identified only by Niklassen et al. Reference Niklassen, Draf, Huart, Hintschich, Bocksberger and Trecca13 on a small series of 31 patients, with a residual dysfunction recorded in only 6.5 per cent of cases.
Given the high prevalence of the SARS-CoV-2 infection in the general population, these incidence rates mean that hundreds of thousands of patients worldwide will need care for permanent severe chemosensory disorders in the coming years. It is therefore essential to provide the colleagues who will face these problems in the future with reliable data in order to enable them to correctly inform their patients. On the basis of the present study, it is possible to state that the spontaneous recovery margins of a chemosensitive disorder, especially if severe, after two months from clinical onset are very poor. For this reason, we do not consider that there are any reasons to further delay any specific treatmentReference Vaira, Hopkins, Petrocelli, Lechien, Cutrupi and Salzano22,Reference Le Bon, Konopnicki, Pisarski, Prunier, Lechien and Horoi23,Reference Whitcroft and Hummel27 beyond this time limit.
To date, there are only a few therapeutic trials for olfactory dysfunctions in Covid-19 patients. Some authors reported that systemic steroids and steroid rinses may be effective in the management of Covid-19 related olfactory dysfunctions.Reference Vaira, Hopkins, Petrocelli, Lechien, Cutrupi and Salzano22,Reference Le Bon, Konopnicki, Pisarski, Prunier, Lechien and Horoi23,Reference Whitcroft and Hummel27,Reference Hopkins, Alanin and Philpott28 Furthermore, olfactory training is recommended to Covid-19 patients with loss of smell for more than two weeks.Reference Hopkins, Alanin and Philpott28 The efficacy of alpha-lipoic acid, omega-3 supplements and retinoic acid derivatives has not yet found unequivocal indications that recommend their use in patients with Covid-19 related olfactory dysfunctions.Reference Whitcroft and Hummel27,Reference Hopkins, Alanin and Philpott28
Neither in this nor in any other studies already published has it been possible to detect any risk factors significantly related to the development of a long-term disorder. The significant correlation found between persistent olfactory disorder and age may be related to the normal higher frequency of these dysfunctions in the elderly population.Reference Landis, Konnerth and Hummel29 However, this correlation was not reported in the previous studiesReference Lechien, Chiesa-Estomba, Beckers, Mustin, Ducarme and Journe11–Reference Niklassen, Draf, Huart, Hintschich, Bocksberger and Trecca13 and may therefore be related to a lower regenerative capacity of the olfactory epithelium in older patients.Reference Kondo, Kikuta, Ueha, Suzukawa and Yamasoba30
These findings reflect the great uncertainty that still surrounds the exact pathogenesis of chemosensitive disorders during SARS-CoV-2 infection, the severity and duration of which seem to be related to individual factors not yet identified.Reference Cho, To, Yeung, Tso, Fung and Chau31–Reference Le Bon and Horoi35 However, we have detected that patients presenting with a partial disorder at baseline (i.e. hyposmia of varying degrees of severity) usually achieve a complete recovery whereas persistent disorders only affect patients with complete anosmia at clinical onset.
The main limitation of this study is the impossibility of establishing how many of the patients who presented with olfactory dysfunction at six months already had this problem even before infection. The evaluation of patients prior to infection was obviously impossible, but the inclusion of a control group could have been useful in establishing the extent of this bias. Moreover, the six-month follow up is still too short to assess long-term recoveries. In fact, recoveries of some post-viral olfactory dysfunctions have been reported after more than a year after onset.Reference Lee, Lee, Wee and Kim17
• The long-term chemosensitive recovery rate after coronavirus disease 2019 (Covid-19) has not been clarified
• This study aimed to establish the functional recovery rate by objectively evaluating 300 Covid-19 patients for up to 6 months
• At 6 months, 27 and 10 per cent of the patients had residual olfactory or gustatory disturbance, respectively
• Functional recovery is significant in the first month in relation to taste and first two months in relation to smell
• After this period, the likelihood of improvement is significantly reduced
• This time limit indicates the period when specific therapies must be initiated for Covid-19 related chemosensitive disorder
Another limitation of the study was the inclusion of only mild-to-moderate Covid-19 patients in home isolation. In fact, the test is not applicable to hospitalised patients who do not have the possibility of accessing the odorants necessary for carrying out the self-administered test. These patients were evaluated with the Connecticut Chemosensory Clinical Research Center test and included in other studies.Reference Vaira, Lechien, Khalife, Petrocelli, Hans and Distinguin1,Reference Vaira, Hopkins, Salzano, Petrocelli, Melis and Cucurullo21
Conclusion
Six months after the onset of Covid-19, about 6 per cent of patients still have a severe persistent olfactory or gustatory disturbance. The functional recovery is significant in the first month in relation to taste and in the first two months in relation to smell. After this period, the likelihood of improvement is significantly reduced. This time limit ideally represents the period when specific therapies must be initiated in order to prevent the persistence of Covid-19 related chemosensitive disorders.
Acknowledgements
The authors would like to thank all the patients who were involved in this study. The adhesion of the patients was exceptional and enthusiastic and allowed us to bring all 300 people enrolled to conclude the 6-month follow up.
Competing interests
None declared
